Antihistamines are drugs that block the action of histamine (a compound released in allergic inflammatory reactions) at the H1 receptor sites. They are responsible for immediate hypersensitivity reactions such as sneezing and itching. Members of this class of drugs may also be used for their side effects, including sedation and antiemesis (prevention of nausea and vomiting). Antihistamines provide their primary action by blocking histamine H1 at the receptor site. They have no effect on rate of histamine release, nor do they inactivate histamine.
Dimenhydrinate is primarily an ethanolamine-class antihistamine drug, i.e. a H1 antagonist but it possesses an antimuscarinic effect as well. Due to its antiemetic properties it is used to prevent the symptoms of motion sickness, vertigo, nausea after surgery and morning sickness during pregnancy. Moreover, it can be beneficial in vestibular disturbances and other types of true vertigo. Diphenhydrimine has also been used to reverse the extrapyramidal side effects caused by phenothiazines. One of the main characteristics of this compound is its pronounced tendency to induce sedation.
Chemically, Dimenhydrinate is a salt of two drugs, namely diphenhydramine and 8-chlorotheophylline which is a chlorinated derivative of the theophylline. Theophylline is very closely related to caffeine and theobromine, mild central nervous system stimulants. It was thought that by combining the antiemetic effects of diphenhydramine with a stimulant, the extreme drowsiness induced by the former could be mitigated somewhat by the latter. The sedation caused by diphenhydramine, however, is substantially stronger than the stimulation caused by chlorotheophyllinate, so the overall effect is still mostly sedating.
Dimenhydrinate has the empirical formula C24H28ClN5O3 representing a molecular weight of 469.96 [g/mol]. The chemical designation is 2-benzhydryloxy-N,N-dimethylethanamine compound with 8-chloro-1,3-dimethyl-7H-purine-2,6-dione. It is a white crystalline, odourless powder. It is freely soluble in ethanol, sparingly soluble in ethyl ether and slightly soluble in water.
The marketed product of Dimenhydrinate is available in the form of syrup, suppositories, capsules, film-coated tablets, chewable tablets and liquid.
In 1989 a study has been carried out in order to evaluate the possible use of the sublingual dosage route in the case of Dimenhydrinate. Said study compared the diphenhydramine kinetics after various route of administration, namely oral, sublingual and intravenous administration and the results of the study conveyed that systemic drug availability after sublingual administration was similar to that following oral administration on an empty stomach.
Various methods are already known for the industrial preparation of oral dosage forms comprising an antihistamine agent such as Dimenhydrinate as an active ingredient due to its useful therapeutical properties.
EP 1 219 291 B1 relates to a texture masked particle comprised of a core containing a bitter compound, such as Dimenhydrinate, a first layer of a taste masking agent and a second layer on the surface of the first layer containing a film forming polymer and an anti-grit agent. Chewable tablets made from these coated particles have good taste and exhibit an immediate release profile.
WO 2007/041367 A1 refers to an oral composition comprising Dimenhydrinate and a salivation inducing agent such as muscarinic acetylcholine receptor agonists, cholinesterase inhibitors, N,N-disubstituted phenalkylamines Saliva production is increased during ingestion, improving therefore the swallowability of such dosage forms. The dosage form is selected among chewable tablet, thin film strip, foam tablet and gummy.
US-A-2006/127479 discloses a taste masked pharmaceutical composition comprising a bitter tasting drug such as Dimenhydrinate prepared without using an organic solvent. Organic solvents have various effects on human health and may also pose a safety risk in the workplace.
Although each of the above patents represents an attempt to provide a pharmaceuticals compositions comprising Dimenhydrinate easy to swallow and thus accessible to patients with swallowing difficulties, there still exists a need for a sublingual tablet, particularly beneficial in patients who are unable to tolerate swallowing and in case of emergences due to the rapid absorption and onset of action.